tbuckley/cabot-search huggingface dataset:
Prognostic indicators of KRAS G12X mutations in pancreatic cancer.
Authors: Bach Ardalan, Aaron Ciner, Yasmine Baca, Sourat Darabi, Anup Kasi, Emil Lou, Jose Ignacio Azqueta, Joanne Xiu, Chadi Nabhan, Anthony Frank Shields, Michael J. Pishvaian, Wolfgang Michael Korn, Sanjay Goel
Journal: Journal of Clinical Oncology (2023)

735 Background: We have studied the role of KRAS mutations in relation to the prognosis in patients with advanced pancreatic ductal adenocarcinoma (PDAC). KRAS is a well-described oncogenic driver in PDAC, with mutations identified in over 90% of cases, typically involving codon 12. The three predominant missense variants include G12D, G12V and G12R. PDAC has the highest rate of G12R mutations compared to other malignancies, comprising 15-20% of KRAS-mutated tumors. This study presents a new finding in the progression of advanced PDAC utilizing a large clinical and genomic database to further characterize the clinical features of pathogenic KRAS variants in PDAC with a focus on G12R. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X 2 and Fisher-Exact and p adjusted for multiple comparisons (q) was &lt; 0.05 (Benjamini-Hochberg). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of specific treatments; comparison was done by Kaplan-Meier test. Results: A total of 5,555 patients with PDAC harboring either KRAS G12D (n = 2,671), G12V (n = 1,871) G12R (n = 904) or G12C (n = 109) variants were identified. The patients with KRAS G12R mutant tumors had significantly longer median real-world overall survival (mRWOS) compared to G12D (452 vs 358 days, HR 0.82, CI 0.74 – 0.9, p &lt; 0.0001). This difference persisted regardless of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel. There was no difference in outcomesbetween patients with KRAS G12R, G12V or G12C. PD-L1 expression was significantly lower in G12R than in G12C or G12D (13% vs 27% vs 19%,) while the prevalence of TMB-H and dMMR was comparable across isoforms. Conclusions: Patients with KRAS G12R variants has improved rwOS compared to G12D irrespective of the chemotherapy regimen administered. Immune profiling suggested that the immune contexture in G12R-driven tumors are distinct from G12D as reflected by reduced PDL1 staining, decreased levels of multiple checkpoint receptors. We aim to further explore the molecular basis for these differences with a focus on PI3K and MAPK pathways. Based on this data, survivorship studies in patients with advanced PDAC should consider reporting KRAS mutational status.
Exploring optimal therapeutic management of STAGE IA PDAC in the era of neoadjuvant chemotherapy.
Authors: Marina Macchini, Giulio Belfiori, Stefano Crippa, Giulia Orsi, Giulia Gasparini, Domenico Tamburrino, Marco Schiavolena, Gabriele Capurso, Massimo Falconi, Michele Reni
Journal: Journal of Clinical Oncology (2023)

712 Background: Neoadjuvant chemotherapy (NAT) is currently recommended for non-metastatic pancreatic ductal adenocarcinoma (PDAC). Data on the optimal NAT duration and the proper post-surgical chemotherapy (PSC) are lacking, especially for patients (pts) who yielded a pathological stage IA. Methods: We retrospectively analyzed the outcome of PDAC pts resected between 2015 and 2020 at our institution after NAT yielding a pathologic stage of PDAC ypT1N0. Pts were analyzed basing on NAT duration (aim 1) and PSC indication (yes/no) and type (aim 2). The primary endpoint was median event-free survival (EFS) for aim 1 and median disease free-survival (DFS) for aim 2. As per secondary endpoints, overall survival (OS) and the prognostic role of clinical and pathological variables was assessed (baseline CA19.9 level; pre-operative Ca19.9 level, basal vascular involvement, grading, perineural invasion, R1 resection). Results: During the study period a total of 756 pts were resected, 363 (48%) after NAT. Of them, 72 pts (20%) achieved a pathological ypT1N0 (ypIA). Among this group 16 pts (22%) showed a T1a-T1b, 62 pts (86%) had a G1/G2 tumor, 60 pts (83%) had a R0, 36 pts (50%) had a perineural invasion and 33 (46%) had a tumor regression grade marked or completed. For aim 1 we compared 34 pts (47%) treated with NAT for not more than 4 months (Group A1) and 38 pts (53%) treated for at least 4 months (Group B1). Baseline, biochemical and radiological variables were similar between the 2 groups. No statistical difference was found in EFS (Group A1: median 46 months/ Group B1: median not reached). For aim 2 we compared 10 pts (14%) who received the same chemotherapy regimen in NAT and PSC (Group A2), 35 pts (49%) who received a different chemotherapy regimen in NAT and PSC (Group B2) and 27 (14%) pts who did not receive any PSC (Group C2). PSC were gemcitabine/nab-paclitaxel (10%) and mFOLFIRINOX (90%) in group A2, whereas gemcitabine/nab-paclitaxel (17%), mFOLFIRINOX (3%), gemcitabine (51.5%), capecitabine (17%), gemcitabine/capecitabine (8.5%), PEXG (3%) in group B2. DFS were 24 months for group B2, whereas median was not reached for group A2 e C2 (p=0.006). No statistical difference was found in OS among the groups. At multivariate analysis only grading (G3) emerged as independent factor for poor prognosis. Conclusions: In ypIA pts NAT duration and or type seem to be unrelated to the outcome. PSC performed with alternative and depotentiated chemotherapy as compared to NAT, seem to be related to a higher rate of disease recurrence. Poor differentiated/G3 tumors is confirmed as independent risk factor for poor survival in this population.
INTEGRATE IIa: A randomised, double-blind, phase III study of regorafenib versus placebo in refractory advanced gastro-oesophageal cancer (AGOC)—A study led by the Australasian Gastro-intestinal Trials Group (AGITG).
Authors: Nick Pavlakis, Kohei Shitara, Katrin Marie Sjoquist, Andrew James Martin, Anthony Jaworski, Sonia Yip, Yung-Jue Bang, Thierry Alcindor, Christopher J. O'Callaghan, Niall C. Tebbutt, Andrew Strickland, Sun Young Rha, Keun-Wook Lee, John Raymond Zalcberg, Timothy Jay Price, John Simes, David Goldstein
Journal: Journal of Clinical Oncology (2023)

LBA294 Background: AGOC has limited options after second-line therapy. Regorafenib (Rego), an oral multi-targeted tyrosine kinase inhibitor (TKI) targeting angiogenic, stromal and oncogenic receptor TKs, prolonged progression free survival (PFS) versus placebo (PBO) across all regions/subgroups in the INTEGRATE phase 2 randomised trial (JCO 2016 43(23):2728-2735). INTEGRATE IIa was designed to examine if Rego improves overall survival (OS). Methods: Double-blind placebo-controlled phase 3 trial comparing Rego + best supportive care (BSC) vs PBO + BSC using 2:1 randomisation, stratified by tumour location (GO junction vs gastric), geographic region (Asia vs rest of world), prior VEGF inhibitors (Y/N). Eligibility criteria: histologically/cytologically confirmed AGOC, evaluable metastatic/locally advanced disease, failure/intolerance of ≥ 2 prior lines of therapy with a platinum agent + fluoropyrimidine. Primary objective: OS in the whole study population. OS among Asian sub-population is a key secondary objective. Target of at least 221 events from 250 patients provides 80% power to detect an OS hazard ratio (HR) of 0.67. Pooled OS analysis incorporating INTEGRATE phase 2 data is also planned. Secondary endpoints include PFS, objective response rate, safety and quality of life. Results: 251 patients enrolled (Oct16 - Sep21) from 5 countries:157 from Asia (Korea, Taiwan, Japan);169 Rego and 82 PBO. After 238 events, median OS (in months) for Rego vs PBO was 4.5 vs 4.0 (HR 0.70 [95%CI: 0.53 to 0.92]; p = 0.011) in the whole study population, with a 12 mo survival of 19% vs 6%. Median PFS was 1.8 v 1.6 (HR = 0.52; [95%CI: 0.40-0.69]; p = &lt; .0001). After pre-planned adjustment for multiplicity, there were no statistically significant differences across regions (Asia versus non-Asia) or other pre-specified subgroups. Pooled analysis median OS was 5.0 v 4.1 (HR 0.69 [95% CI:0.56 to 0.87]; p = 0.001). Rego toxicity was similar to previously reported. Conclusions: Rego improves survival compared with PBO in advanced refractory AGOC, offering a new treatment option. This result creates a therapeutic platform for combination studies. INTEGRATE IIb is an ongoing international randomised Phase 3 trial in pre-treated patients with AGOC comparing Rego + nivolumab to standard chemotherapy (NCT0487936). Clinical trial information: NCT02773524 .
Effect of PD-1 inhibition on macrophage population in human tissue cultures.
Authors: Ngoc Hoang, Charlotte Welling, Marlon Husstegge, Justus Koerfer, Astrid Monecke, Arved Weimann, Ines Gockel, Florian Lordick, Sonja Kallendrusch
Journal: Journal of Clinical Oncology (2023)

463 Background: Moderate response rates of PD-1 inhibition in gastric and esophagogastric junction cancers (GC/EGJC) urge for reliable biomarkers. To further improve treatment outcomes, patients need targeted therapy based on clinically relevant biomarkers and predictive test systems for assessing individual drug susceptibility. We have previously established patient derived tissue cultures (PDTC) as a comprehensive ex-vivo drug testing system for GC/EGJC patients. Methods: The standardized PDTC) model was developed using tissue from surgical resection specimens to investigate response to the PD-1 inhibitor Nivolumab and the macrophage depriving bisphosphonates clodronate and zoledronic acid. Resident macrophage population (CD68, CD163), tumor proliferation (Ki67) and apoptosis (cPARP), as well as bulk gene expression data (nanoString technology) were analysed after 72 hours of PD-1 inhibition. Additionally, supernatants were collected, and cytokine concentrations are measured based on Luminex technology. Results: Macrophage depletion could lead to enhanced anti-tumoral effects in PDTCs after PD-1 inhibition. Gene signatures for Interferon γ-mediated inflammation and myeloid cell activity were identified and found to be relevant indicators for tissue response upon immune checkpoint inhibition. We observed alterations in cytokine and soluble surface marker concentrations, such as IL-8, IL-17A and IL-23 or PD-L2, LAG3 and CTLA4. Conclusions: Yielding an organotypic cell composition, we were able to demonstrate individual response patterns and immunological characteristics to identify responsiveness to PD-1 inhibition in GC and EGJC tissue. PDTCs are potent to define biological marker sets ex vivo and to differentiate and predict clinical patient response as well as their inherent immune cell capacity and plasticity.
Clinical and molecular presentation of KRAS G12D-mutated pancreatic ductal adenocarcinoma in real-world settings.
Authors: Emma G. Sturgill, Sahiti Kolli, Kavanya Feustel, Daniel Luckett, Carissa Jones, Marilyn Elaine Holt, Annastasia Hyde, Suzanne Fields Jones, Cesar Augusto Perez, Judy S. Wang, Stephen G. Divers, Meredith Pelster, Jason Timothy Henry, David R. Spigel, Howard A. Burris III, Andrew Jacob McKenzie
Journal: Journal of Clinical Oncology (2023)

738 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRAS WT (26%), KRAS G12D (31%), and KRAS non-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRAS G12D and KRAS non-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( &gt; 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; &lt; 5% frequency occurrence). KRAS G12D exhibited significantly decreased overall survival compared to KRAS WT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRAS WT ], 20.1 months (17.0-22.7 months) [ KRAS G12D ], 21.7 months (20.0-25.0 months) [ KRAS non-G12D ]; Cox model p-value &lt; 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRAS non-G12D and KRAS WT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRAS WT ], 7.8 months (7.3-8.7 months) [ KRAS G12D ], 9.8 months (8.8-11.1 months) [ KRAS non-G12D ]; Cox model p-value &lt; 0.01). Within the KRAS G12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.
Novel blood-based biomarker candidates in screening for colorectal cancer.
Authors: Jason Lee Liggett, Mathias M Petersen, Jakob Kleif, Morten Rasmussen, Lars Nannestad Jørgensen, Jakob Benedict Seidelin, Mogens R. Madsen, Jesper Vilandt, Kåre Andersson Gotschalck, Lars M. Andersen, Ali Khalid, Berit Andersen, Ib Jarle Christensen, Herbert A. Fritsche, Eric S. Mayer, Christina Therkildsen
Journal: Journal of Clinical Oncology (2023)

244 Background: Colorectal cancer (CRC) is the third most common cancer worldwide motivating national screening strategies utilizing fecal immunochemical tests (FIT). Blood-based biomarkers could be an alternative method to increase compliance in population-based screening programs for early detection of CRC. We aimed to identify new blood-based biomarkers that could be potential candidates for use in colorectal cancer screening. Methods: In a nested cohort study of 1967 FIT positive participants of the Danish CRC screening program serum levels of GDF-15, hepsin, IL-8, keratin1-10, L1CAM, MIA, monocyte MCP-1, NSE and OPG were measured using the Luminex xMAP immunoassay platform. Main outcomes were CRC vs non-CRC and CRC, high-risk adenomas (HRA) or medium-risk adenomas (MRA) vs low-risk adenomas (LRA) or clean colorectum. Odds ratios for associations between biomarker expressions and outcomes were calculated using logistic regression models and visualized by area under the receiver operating characteristic (ROC) curve (AUC). Analyses were made on the Luminex biomarkers alone and with addition of clinical and demographic information. Results: FIT-induced colonoscopies detected 240 CRCs and 625 HRA or MRA. Multivariate analyses using all biomarkers and age found hepsin, IL-8 and OPG significantly (p&lt;0.001) associated in relation to the main outcome (CRC vs non-CRC) with odds ratios of 0.74 [0.59-0.92], 2.59 [2.12-3.15] and 0.90 [0.82-0.99], respectively. The full model using all biomarkers and age presented an AUC of 0.73 [0.70-0.77]. Conclusions: Changed serum levels of nine novel biomarkers seem to be potential predictors for early detection of CRC, especially hepsin, IL-8 and OPG. [Table: see text]
Effects of gene expression in 5-FU metabolic pathways in a phase III trial evaluating adjuvant S-1 therapy compared to surgery alone following curative resection for biliary tract cancer (JCOG1202A1).
Authors: Shuichi Mitsunaga, Masafumi Ikeda, Shogo Nomura, Chigusa Morizane, Akiko Todaka, Keiko Kamei, Hiroo Yanagibashi, Nobumasa Mizuno, Kunihito Gotoh, Yasuyuki Kawamoto, Hirofumi Shirakawa, Naohiro Okano, Tatsuya Nomura, Amane Takahashi, Isamu Makino, Yoshiyasu Anbo, Koji Ohta, Hiroshi Katayama, Masaru Konishi, Makoto Ueno
Journal: Journal of Clinical Oncology (2023)

732 Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy in Japanese patients with resected biliary tract cancer (BTC), based on the results of JCOG1202, a phase III trial evaluating adjuvant S-1 following curative resection for BTC compared to surgery alone. The efficacy of 5-FU-based therapy is related to the expression of enzymes involved in 5-FU metabolic pathways, such as thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD). The aim of this study was to evaluate the impact of messenger RNA (mRNA) levels of the four 5-FU metabolic pathway genes on the outcomes of patients enrolled in JCOG1202. Methods: Tumor cell RNA was isolated from formalin-fixed paraffin-embedded primary BTC specimens resected in 264 of 440 randomized patients in JCOG1202. The four 5-FU metabolic pathway genes were measured in 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89) who were randomly divided to training (n = 96) or validation set (n = 87). The endpoints of interest were the predictive values of the four genes for the efficacy of adjuvant S-1 on overall survival and relapse-free survival (RFS), and we here report the results regarding RFS. Cut-off levels for mRNA expression were selected in the training set which minimized the bootstrap p-values (2,000 samples) of an interaction term of treatment (surgery alone or S-1) and mRNA expression in a Cox regression model. Results: There were no obvious differences in each mRNA level and clinical characteristics between surgery alone and adjuvant S-1 groups. RFS tended to be better with adjuvant S-1 (hazard ratio [HR] = 0.790, [95% confidence interval: 0.524-1.192]) compared to surgery alone, which was maintained in the low DPD population (HR = 0.440 [0.216-0.898] in training set and 0.748 [0.334-1.675] in validation set), in the low TP population (HR = 0.709 [0.388-1.296] and 0.602 [0.287-1.262]), and in the high OPRT population (HR = 0.520 [0.152-1.779] and 0.609 [0.161-2.304]). Conclusions: The efficacy of adjuvant S-1 on RFS was representative in BTC patients with intratumoral gene expressions of low DPD, low TP, and high OPRT, which was disappeared in the population with high DPD, high TP, and low OPRT. These biomarkers might be useful to predict therapeutic benefits with S-1 containing chemotherapy for BTC.
A phase II biomarker-oriented study to evaluate paclitaxel, olaparib, and durvalumab combination in patients with advanced gastric cancer.
Authors: Tae-Yong Kim, Jeesun Yoon, Dae-Won Lee, Seock-Ah Im, Ah-Rong Nam, Ju-Hee Bang, Kyoung-Seok Oh, Jae-Min Kim, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Do-Youn Oh
Journal: Journal of Clinical Oncology (2023)

404 Background: DNA damage response (DDR) gene alterations are observed in 27% of gastric cancer (GC), therefore, targeting DDR might be an interesting strategy in GC. Olaparib plus paclitaxel showed numerically improved overall survival (OS) compared to paclitaxel in 2L GC patients (pts), even though it did not meet the endpoint. (Lancet Oncol 2017). Besides DNA damage repair, olaparib induces immune modulation. The role of immune checkpoint inhibitor (ICI) is established in 1L and 3L+ GC. The combination of cytotoxic chemotherapy, DDR acting agent and ICI might have synergistic effects in GC, which has not been tested in clinical studies. Here, we report biomarker-oriented phase II study of paclitaxel/olaparib/durvalumab combination in 2L GC. (NCT03579784). Methods: Advanced GC pts who have failed to 1L chemotherapy were enrolled. During 1st cycle, paclitaxel (80 mg/m 2, D1, 8, 15 Q 4wk) and olaparib (150mg bid, D1-28) was administered. From 2 nd cycle, durvalumab (1500 mg, D1 Q 4wk) was added on them. Tumor biopsy (pretreatment, after 1st cycle, at disease progression) and blood collection (every cycle) was mandatory. Primary endpoint was the disease control rate (DCR). Secondary endpoints included ORR, DoR, PFS, OS and safety. For biomarker study, multiplex IHC, NGS, ctDNA, and cytokines and angiogenic factors analysis were performed. Efficacy analysis set (ES) and safety analysis set (SS) were defined as pts who underwent at least one tumor assessment and all pts who received cycle1 day1 or more, respectively. Results: Fifty pts were enrolled (6 screening fail or withdrawal of consent, 44 in SS, 38 in ES) HER2+ GC were 13.2%. Among 38 in ES, DCR and ORR were 84.1% (95% CI, 72.5-95.7) and 39.5% (95% CI, 24.0-55.0) (1 CR, 14 PR and 17 SD). PFS, DoR and OS were 6.7 (95% CI, 4.5-10.3), 6.5 (95% CI, 5.1-10.7) and 11.4 (95% CI, 9.2-13.2) months. Homologous recombination repair (HRR) genetic alterations (9.6 vs. 5.9 in PFS, p=0.037), high CD8/CD3 ratio (8.8 vs. 3.7 in PFS, p=0.008), high PD-L1 (CPS≥10) (9.6 vs 5.1 in PFS, p=0.031), low ATM IHC (13.3 vs. 9.8 in OS, p=0.066), and low serum IL-6 (12.9 vs. 8.3 in OS, p=0.001) were associated with prolonged PFS or OS. In SS, most adverse events (AEs) were mild, and Gr 3/4 leukopenia and anemia were observed in 52.2% and 31.8%. There were no treatment related AEs resulted in study discontinuation. Conclusions: Paclitaxel/olaparib/durvalumab is a promising combination in 2L GC, and is worth to be further explored, especially in biomarker-enriched patients with HRR, specific T-cells subsets, high PD-L1, low ATM and IL-6. Clinical trial information: NCT03579784 .
Unique microbial biomarkers identified in Nigerian patients with colorectal cancer.
Authors: Miseker Abate, Olusegun Isaac Alatise, Adeleye Dorcas Omisore, Akinwunmi O. Komolafe, Oluwatosin Zainab Omoyiola, Fatimah Biade Abdulkareem, Samuel Adegboyega Olatoke, Ademola Adetoyese Adeyeye, Sulaiman Olayide Agodirin, AbdulRazzaq Oluwagbemiga Lawal, Olalekan Olasehinde, Adedapo Olumide Osinowo, Israel Adeyemi Owoade, Iloba Gabriel Njokanma, Mobolaji A Oludara, T. Peter Kingham, Martin R. Weiser, Chad Vanderbilt
Journal: Journal of Clinical Oncology (2023)

222 Background: The microbiome is an important biomarker associated with the pathogenesis and progression of disease in colorectal cancer (CRC). Genetic, dietary and environmental factors have been implicated in CRC microbial dysbiosis, however geographical distinctions in the microbiome of CRC are largely unknown. In this study, we characterize distinctions in the microbial diversity and microbial enrichment of CRC specimen obtained from a Nigerian and U.S. population. Methods: A validated microbiome bioinformatics pipeline that is generalizable across multiple next generation sequencing platforms was utilized. Microbial profiles for alpha diversity and enrichment were generated for two large, geographically distinct cohorts: (1) U.S. (n=498) and (2) Nigerian (n=65) cohorts. CRC specimen from Nigeria were compared to CRC specimen from the U.S. using the same microbial bioinformatics pipeline and methodology for analysis. Microbial differences stratified based on CRC microsatellite-instability (MSI) status were identified. Results: 9 unique microbial species were significantly enriched in the CRC specimen from the Nigerian cohort when compared to the US cohort. Subset analysis based on MSI status revealed enrichment of Faecalibacterium and Veillonella in the Nigerian cohort for both MSI and microsatellite stable (MSS) CRC (Table). Prevotella was significantly enriched in MSS CRC in the Nigerian cohort (OR=53.35, CI=10.34,275.37, p&lt;0.001). There were no significant differences in alpha diversity between the Nigerian and U.S. cohorts (p&gt;0.05). Conclusions: Several unique species with taxonomic diversity are enriched in Nigerian CRC and can be independently validated based on stratification by MSI status. Given the varied accessibility of diagnostic and therapeutic tools for CRC in these distinct geographical settings, understanding unique microbial biomarkers will provide the landscape to explore key microbial targets for therapy specific to this population.[Table: see text]